(a) Field of the Invention
The present invention relates to novel sulfonamide derivatives having superior matrix metalloproteinase (MMP) inhibiting activity, and novel intermediates thereof, preparation methods thereof, and a pharmaceutical composition comprising the sulfonamide derivatives.
(b) Description of the Related Art
Angiogenesis, a process during which endothelial cells proliferate from existing capillaries to produce novel capillaries, occurs only under normal physiological functions such as during wound healing, ovulation of females, fetal development processes during pregnancy, etc., and it occurs little under normal conditions exclusive of the above conditions in adults. Angiogenesis is strictly controlled by a balance between angiogenic factors and angiogenesis inhibitors (Folkman, J. and Cotran, Int. Rev. Exp. Pathol. 1976, 16. 207-248. Folkman. J. Nat. Med. 1995. 1, 27-31.).
Erroneous control of angiogenesis is known to cause various diseases (Drug Design and Discovery, 1991, 8, 3. Opthalmol. 1995, 102. 1261-1262. Cell, 1996, 86, 353-364, Biochem. Pharmacol. 2001, 61, 2530270.). Diseases related to angiogenesis occurring in pathological conditions include hemangioma; angiofibroma; arteriosclerosis which is a vascular malformation cardiovascular disease; angiostenosis; edematous sclerosis; etc. Eye diseases caused by angiogenesis include corneal transplantation angiogenesis; angiogenic glaucoma; diabetic retinopathy; angiogenic corneal disease; age-related macular degeneration; pterygium; retinal degeneration; retreolental fibroplasias; granular conjunctivitis; etc. Additionally, skin diseases caused by angiogenesis include chronic inflammatory diseases such as arthritis; psoriasis; telangiectasis; granuloma pyogenicum; sebborhoeic dermatitis; acne; etc., and angiogenisis is also related to periodontal disease. In tumors, cancer cells continuously induce new capillary vessels as pathways to receive nutrient and oxygen for growth thereof and discharge of waste material, and thus angiogenisis is indispensable for growth and metastasis of cancer cells.
The process of angiogenesis generally involves decomposition of the basement membrane of blood vessels by protease, formation of vascular lumen by differentiation, proliferation, and migration of endothelial cells, and reconstruction of blood vessels. Protease involved in this process is referred to as matrix metalloproteinase (hereinafter referred to as ‘MMP’ enzyme).
Matrix metalloproteinase (MMP) is an enzyme secreted from cells such as polymorphonuclear neutrophile, macrophage, fibroblast, and bone cells, etc. MMP is known to decompose protein constituents of the extracellular matrix to be involved in wound healing, angiogenesis, pregnancy, decomposition and reconstruction of connective tissue, etc. Overexpression of MMP is known to be a main cause of various diseases including invasion and metastasis of tumors, and arthritis, by unwanted decomposition of connective tissue. The enzyme is involved in various diseases such as arthritis, tumor growth and metastasis, periodontal disease, multiple sclerosis, etc.
MMP enzymes are a family of metalloproteinase, having zinc at their active site, and they decompose and reconstruct proteins such as membrane collagen, aggrecan, fibronectin, and laminin that form structural proteins in an extracellular matrix. Functions of the enzyme in organisms are naturally inhibited by intrinsic tissue inhibitors of metalloprotease (TIMPs), but an imbalance thereof causes overexpression and activation of MMPs to cause decomposition of tissue. Functions of MMPs play important roles in the development of chronic diseases such as multiple sclerosis, arthritis, fibrosis and other inflammation, and growth and metastasis of malignant tumors. For this reason, MMPs are attractive targets as inhibitors of development and treatment of such diseases.
Up to now, 17 kinds of MMP enzymes in humans have been known, and they show many similarities therebetween. They are largely divided into collagenase, stromelysin, gelatinase, matrilysin, metalloelastase, and membrane-type (MT) MMP enzymes.
Epileptic enzyme fibroblast collagenase pertains to MMP-1, and substrates of the enzyme thereof are collagen type I, II, III, VII, VIII, X, and gelatin. 72-Kda gelatinase A pertains to MMP-2, and substrates of the enzyme thereof are gelatin, collagen type IV, V, VII, X, elastin, and fibronectin. Stormelysin-1 pertains to MMP-3, and substrates of the enzyme thereof are proteoglycan, fibronectin, laminin, procolagenase, collagen type IV, V, IX, X, and elastin. Matrilysin pertains to MMP-7, and substrates of the enzyme thereof are proteoglycan, fibronectin, laminin, procolagenase, gelatin, collagen type IV, elastin, and urokinase. Polymorphonuclear leukocyte collagenase pertains to MMP-8, and substrates of the enzyme thereof are the same as those of MMP-1. Stormelysin-2 pertains to MMP-10, and substrates of the enzyme thereof are the same as those of MMP-3. Stormelysin-3 pertains to MMP-11, and substrates of the enzyme thereof are laminin and fibronectin. Macrophage metalloelastase pertains to MMP-12, and substrates of the enzyme thereof are elastin and fibronectin. Up to now, targeted MMPs include MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-13, membrane-type-1-MMP (MT1-MMP), etc.
During carcinogenesis, various MMPs are simultaneously produced to be involved in growth and metastasis of tumors. In metastasis of cancer cells, malignant cancer cells are separated from a primary tumor and produced MMPs to decompose main ingredients of extracellular matrices, collagen, fibronectin, proteoglycan, etc., and cause migration and proliferation of endothelial cells. In this process, MMPs such as MMP-1, MMP-2, MMP9, etc. act. Therefore, inhibitors of these MMP enzymes can be used for a novel anticancer drug blocking growth and metastasis of cancer cells. Collagen, which is a constitutional ingredient of the main protein of an extracellular matrix, maintains its structural form in various tissues and provides physical strength, and is involved in various processes such as cell attachment, migration, differentiation, etc. Turnover of collagen is required for reconstruction of connective tissue during growth and development of cells, and it is involved in arthritis, glomerulonephritis, atherosclerosis, tissue ulceration, periodontal disease, fibrotic lung disease, and pathological processes accompanying invasion and metastasis of cancer cells. Particularly, it has been clarified that during carcinogenesis, in cancer invasion and metastasis stages, MMP-2 and MMP-9 are excessively secreted. MMP-2, which is the enzyme mostly expressed in bodies, decomposes collagen type V, VII, X, fibronectin, elastin, and all forms of unfolded collagen, as well as collagen type IV. Type IV collagenase MMP-2 and MMP-9 decompose type IV collagen, which is a main ingredient of basement membranes, which are the first barrier to cancer metastasis, and they are the most important enzymes involved in invasion and metastasis of cancer cells. Therefore, a type IV collagenase MMP-2 and MMP-9 inhibitor can be used for treatment of cancer invasion and metastasis, and for rheumatoid and periodontal disease, as well as for corneal ulcers caused by decomposition of collagenic connective tissue.
Collagenase that is secreted by fibroblast, polymorphonuclear leukocyte, epithelia, and macrophage cells is an important enzyme in periodontal disease. First, an endotoxin such as lipopolysaccharide is secreted to periodontal tissue due to anaerobic gram negative infection, and thereby tissues are directly destroyed, or cytokines such as interleukin and prostaglandin are secreted because of immunization of bodies, to cause inflammation. Collagen, a matrix of periodontal tissues, is decomposed by collagenase secreted by stimulation of these inflammation media and bacterial collagenase to cause gingival inflammation, which, if left, progresses toward periodontal disease. In addition, MMP-3 and MMP-8 also reduce proteoglycan, which is a main polymer ingredient of connective tissues. Thus, an inhibitor for these enzymes (MMP-3, MMP-8) can also be used for treating periodontal disease.
Arthritis, a representative inflammatory disease, occurs because of autoimmunization, but as the disease progresses, chronic inflammation occurring in the synovial cavity between articulations causes angiogenesis to destroy connective tissues without blood vessels. With the aid of inflammation-causing cytokine, synovial cells and endothelial cells that proliferate in the synovial cavity progress angiogenesis, thereby forming a connective tissue layer, an articular disc, to destroy connective tissues functioning as a cushion (Koch, A. E. Polverini, P, J., Leibovich, S. J., Arthritis Rheum. 1986, 29, 471. Koch, A. E., Arthritis Rheum. 1998, 41, 951); It has been clarified that MMP enzymes decompose the main ingredients of connective tissue, collagen and proteoglycan (Sapolsky, A. I., Keiser, H., Howell, D. S., Woessner, J. F., Jr. J. Clin. Invest. 1976, 58, 1030). They have been cloned from breast cancer cells, and clarified to be involved in arthritis (Freiji, J. M., Diez-Itza, I., Balbin, M., Sanchez, L. M., Blasco, R., Tolivia, J., Lopez-Otin, C., J. Biol. Chem. 1994, 269, 16766). In addition, the main substrate of MMP-13 is type II collagen which is a main constructional ingredient of articular cartilage, and as it has been clarified that a concentration of the enzyme increases in human bone and joint tissues and the enzyme is produced by chondrocyte, it has also been clarified to be involvedd in arthritis, and thus an inhibitor for the enzyme can be used for an arthritis-treating agent.
A TNF-α converting enzyme (TACE) catalyzes formation of TNF-α from a membrane-bound TNF-α protein precursor. TNF-α is a pro-inflamatory-cytokine involved in antitumor processes as well as in rheumatoid arthritis, septic shock, transplantation rejection, insulin tolerance, and HIV inflammation; and it is also known to mediate congestive heart failure, cachexia, anorexia, inflammation, fever, inflammatory disease of the central nervous system and inflammatory bowel disease. It has been proven in a study using transfected animals and an antibody for TNF-α that blocking TNF-α formation inhibits progress of arthritis (Rankin, E. C., Choy, E. H., Kassimos, D., Kingsley, G. H., Sopwith, A. M., Isenberg, D. A., Panayi, G. S. Br. J. Rheurmatol. 1995, 34, 334). Therefore, a low molecular inhibitor for MMP and TACE is expected to have potential for treating various disease symptoms including arthritis.
Eye diseases causing blindness a few hundred times every year are also caused by angiogenesis (Jeffrey, M. I., Takayuki, A., J. Clin. Invest. 1999, 103, 1231). Diseases such as macular degeneration occurring in old persons, diabetic retinopathy, retinopathy of prematurity, angiogenic glaucoma, and corneal disease of angiogenesis are caused by angiogenesis (Adamin, A. P., Aiello, L. P., D'Amato, R. A., Angiogenesis 1999, 3, 9). Diabetic retinopathy is a complication of diabetes, wherein capillaries in retina infiltrate into the vitreous body by angiogenesis to cause blindness. Eyes are tissue without blood vessels, and growth of blood vessels causes blindness. Eye disease caused by angiogenesis has no appropriate treating agent, and presently, steroids or antibiotics are used. If the disease is more progressed, blood vessels are cauterized or photocoagulated, but the effects are temporary and cannot block proliferation of blood vessels, and thus the disease relapses. Therefore, the most basic treatment method is to block angiogenesis.
Additionally, psoriasis characterized by red spots and scale on the skin is a chronic proliferatory skin disease, and this is also not easily healed and it involves pain and malformation. For an ordinary person, horny cells(or corneocyte) proliferate once a month, while for a patent with psoriasis, they proliferate at least once a week. For such fast proliferation, a great deal of blood must be supplied, and thus angiogenesis actively occurs (Folkman, J. J. Invest. Dermatol. 1972, 59, 40). Thus, an angiogenesis inhibitor can be used as a novel treating agent of dermatological diseases such psoriasis.
It is known that since the proteinases are involved in various physiological processes such as embryogenesis, tissue formation, salivary gland formation, odontogenesis, etc., they are involved in various diseases of pathological processes such as cancer metastasis, periodontal disease, rheumatoid arthritis, inflammation, hyperparathyroidism, diabetes, corneal ulcers, osteoporosis, stomach ulcers, wounds, wrinkles, acne, AIDS, burns, arteriosclerosis, bone fractures, etc.
MMP inhibitors that can be used for treating agents of various diseases have been subject to many patents and patent applications, as follows. Specifically, they are described in U.S. Pat. No. 5,189,178; U.S. Pat. No. 5,455,258; U.S. Pat. No. 5,506,242; U.S. Pat. No. 5,672,615; U.S. Pat. No. 5,756,545; U.S. Pat. No. 5,804,593; U.S. Pat. No. 5,817,822; U.S. Pat. No. 5,859,061; U.S. Pat. No. 5,861,510; U.S. Pat. No. 5,962,471; U.S. Pat. No. 5,985,900; U.S. Pat. No. 6,022,873; U.S. Pat. No. 6,022,893; U.S. Pat. No. 6,071,903; U.S. Pat. No. 6,121,272; U.S. Pat. No. 6,143,744; U.S. Pat. No. 6,150,394; U.S. Pat. No. 6,153,612; U.S. Pat. No. 6,156,798; U.S. Pat. No. 6,159,995; and U.S. Pat. No. 6,612, 821.
As explained, through recent studies of MMP inhibitors, efforts to prevent and treat various diseases and pathological processes such as cancer metastasis, periodontal disease, rheumatoid arthritis, inflammation, hyperparathyroidism, diabetes, corneal ulcers, osteoporosis, stomach ulcers, wounds, wrinkles, acne, AIDS, burns, arteriosclerosis, bone fractures, etc. have been extensively made, but satisfactory effects for inhibiting MMP have not been obtained.